Dl-octahydro-8beta-(t-butoxy or benzyloxy)-8abeta-lower alkyl-2(3h)-phenanthrones

ABSTRACT

THE DISCLOSURE DESCRIBES COMPOUNDS OF THE CLASS OF DL2,3,4,4AB,4BA,5,6,7,8,8A-DECAHYDRO-8AB-LOWER ALKYL - 8B(T-BUTOXY OR BENZYLOXY)-2-OXO-1 - SUBSTITUTED - PHENANTHRENES USEFUL AS INTERMEDIATES IN THE SYNTHESIS OF BIOLOGICALLY ACTIVE STEROID MOIETIES.

United States Patent Int. Cl. C07c 49/00 US. Cl. 260-586H 3 ClaimsABSTRACT OF THE DISCLOSURE This disclosure describes compounds of theclass of dl- 2,3,4,4a,8,4bu,5,6,7,8,8a-decahydro-8afi-lower alkyl 8 8-(t-butoxy or benzyloxy)-2-oxo-1 substituted phenanthrenes useful asintermediates in the synthesis of biologically active steroid moieties.

CROSS REFERENCE TO RELATED APPLICATION This application is a division ofmy copending application Ser. 'No. 372,690, filed June 7, 1964, now Pat.No. 3,446,849.

BRIEF SUMMARY OF THE INVENTION wherein R is selected from the groupconsisting of benzyl and tertiary butyl, R is lower alkyl and X isselected from the group consisting of H n o g I HO I and no CCHgCHz-DETAILED DESCRIPTION OF THE INVENTION The compounds of the presentinvention are usually viscous oils or crystalline solids.

ice

Among the compounds within the scope of the present invention are thefollowing:

d1-8fl-t-butoxy-8afl-methyl-4,4afi,4ba,5,6,7,8,8a-octahydro-2 (3 H)-phenanthrone;dl-SB-t-butoxy-8afi-ethyl-4,4afi,4ba,5,6,7,8,8aoctahydro-Z (3H)-phenanthrone; d1-8/3-benzyloxy-8afl-methyl-4,4a,8,4ba,5,6,7,8,8a-0ctahydro-Z 3H -phenanthrone;d1-Sfi-benzyloxy-8aB-ethyl-4,4ap,4ba,5,6,7,8,8a-octahydro-2 3 H-phenanthrone dl-8/i-benzyloxy-8afi,1-dimethy1-4,4a 3,4ba,5,6,7,8,8a-

octahydro-Z (3 H) -phenanthrone;dl-8-benzyloxy-8afl-ethyl-l-methyl-4,4a{3-,4ba-5,6,7,8,-8a-

octahydro-Z (3H -phenanthrone;dl-SB-t-butoxy-Safi,1-dimethyl-4,4afi,4ba,5,6,7,8,8a-

octahydro-2( 3H -phenanthrone;dl-8/3-t-butoxy-8afl-ethyll-methyl-4,4ap,4ba,5,6,7,8,8a

octahydro-2( 3 H) -phenanthrone;d1-2,3,4,4a/5',4ba,5,6,7,8,8a-decahydro-8afl-methyl-8p-tbutoxy-Z-oxo-phenanthrene-lpropionicacid; dl-2,3 ,4,4a{3,4ba,5,6,7,8,Sa-decahyro-8aB-ethyl-8fi-tbutoxy-2oxo-phenanthrene-l-propionicacid; (ll-2,3 ,4,4a;3,4boc,5,6,7,8,8a-decahydro-8afl-methyl-85-benzyloxy-2-0xo-phenanthrenel-propionic acid;dl-2,3,4,4a/8,4ba5,6,7,8,8a-decahydro-8aB-ethyl-8flbenzyloxy-Z-oxo-phenanthrene-l-propionicacid and the like.

The present compounds are prepared by using starting materials such as,for example, 2-lower alkylcyclohexane- 1,3-dione (compound I) in theflowsheet hereinafter which is reacted with methylvinyl ketone in thepresence of an alkali metal hydroxide in alcohol and adding to thismixture benzene and pyrrolidine to form a l,6-dioxo-A -9 loweralkyloctalin (II). This material (II) is separated from the mixture andthen treated with sodium borohydride (preferably purified) in alcohol,preferably ethanol, to form a 1-hydroxy-6-oxo-A -9-lower alkyloctalin(III) which is separated from the mixture. This product (III) is thenconverted to 1-acyloxy-6-oxo-A -9-lower alkyloctalin (IV) by reaction ofsaid material (compounds III) with an acyl halide or an acyl anhydride,preferably acetic anhydride, and pyridine. This material (compounds IV)is then separated from the reaction mixture. Reaction of 1-acyloxy-6-ox0-9-lower alky1-A octalin (IV) with a lower alkylorthoformate, preferably ethyl orthoformate, in the presence of a strongacid catalyst will form new enol ethers. For example, when ethylorthoformate is used in the above reaction, 1-acy1oxy-6- ethoxy-9-loweralkyl-A hexahydronaphthalene is formed in quantitative yield. The crudeenol ether (V) 1-acyloxy-6-lower alkoxy-9-lower alky1-A-hexahydr-onaphthalene may then be hydrogenated catalytically t0 the newcompound l-acyloxy-6-lower alkoxy-9-1ower alkyl-trans-A -octalin (VI),which without purification, is warmed with 50% aqueous acetic acid togive l-acyloxy- 6-oxo-9-lower alkyl-trans-Decalin (VII). The subjectmatter shown hereinafter in the fiowsheet as compounds IV through VII isdescribed and claimed in my copending application Ser. No. 360,404,filed Apr. 16, 1964, now US. Pat. No. 3,331,856.

The 1-acyloxy-6-oxo-9-lower alkyl-trans-Decalin compound (VII) whenrefluxed with ethylene glycol and ptoluene-sulphonic acid in a solvent,yields 1-acyloxy-6,6- ethylenedioxy-9-lower alkyl-trans-Decalin (XII)which in turn is readily converted to 6,6-ethylenedioxy-l-hydroxy-9-lower alkyl-trans-Decalin (XIII) by refluxing with an alcoholicsolution of an alkali metal hydroxide, preferably ethanolic potassiumhydroxyide.

When a 1-hydroxy-6,6-ethylenedioxy-9-lower alkyltrans-Decalin (compoundXIII) is heated with benzyl chloride and sodium hydride, an excellentyield of the 1- benzyloxy (compound XIV) derivative is formed. As anexample, 1 hydroxy 6,6 ethylenedioxy-9-methyl-trans- Decalin with benzylchloride and sodium hydride yields1-benzyloxy-6,6-ethylenedioxy-9-methyl-trans-Decalin.

Hydrolysis of the 6,6-ethylenedioxy ketal function (compounds XIV) isreadily accomplished by warming the ketal with aqueous acetic acid.Mineral acids in an organic solvent miscible with water can also beused. As a specific example, when 1-benzyloxy-6,6-ethylenedioxy-9-methyl-trans-Decalin (compound XIV) is warmed with 30% aqueous aceticacid, the product obtained in excellent yield is1-benzyloxy-6-oxo-9-methyI-trans-Decalin (compound XV).

When the compounds, represented by Formula XV, in an inert solvent,preferably chloroform, are treated with bromine in the same solvent, anexcellent yield of the corresponding bromo derivative (XVI) is formed.As a specific example, when 1-benzyloxy-6-oxo-9-methyl-trans- Decalin istreated with bromine in chloroform, a good yield of 1 benzyloxy 7br0mo-6-oxo-9 methyl trans- Decalin is formed.

The bromo compounds (XVI) are dehydrobrominated in excellent yields byheating under reflux a solution of (XVI) in dry dimethylformarnidecontaining anhydrous lithium halide, preferably lithium chloride, andanhydrous lithium carbonate in an inert atmosphere. Such reactionyields, for example, 1-benzyloxy-6-oxo-9-lower alkyl-A trans-octalin(XVII). For example, when 1-benzyloxy-7- bromo-6-oxo-9-methyl transDecalin is dehydrobrominated in dimethylformarnide in the presence oflithium chloride and lithium carbonate, an excellentyield of 1-benzyloxy-6-oxo-9-methyl-A' -trans-octalin is formed.

By the different route, the 1-acyloxy-6-oxo-9-lower alkyl-trans-Decalins(VII) of the general formula:

OCOR' 2 l wherein R is lower alkyl and R is selected from the groupconsisting of hydrogen, lower alkyl, phenyl and substituted phenylradicals (i.e. tolyl, halophenyl, and the like), is dissolved in aninert solvent, preferably chloroform, bromine, preferably dissolved inthe same solvent, is then admixed with this solution to yield thecorresponding bromo derivative, for example, l-lower alkanoyloxy 7 bromo6- 0x0 9-lower alkyl-trans-Decalin (VIII).

Dehydrobromination of this product is carried out by heating a solutionof product (VIII) in dimethylformamide with a lithium halide, preferablylithium chloride, and preferably in the presence of lithium carbonate,thereby yielding the corresponding A derivative (IX). Hydrolysis of thislatter product (IX) is carried out with a weak base, preferablypotassium bicarbonate, a mixture of water and an inert organic solvent,preferably ethanol, miscible with water to yield the correspondingl-hydroxy derivative (X) of the flowsheet hereinafter.

The 1-t-butoxy-6-oxo-9-lower alkyl-N-trans-octalin (XI) is formed byreaction of the above-identified l-hydroxy derivative (X) withisobutylene in an inert solvent, preferably methylene chloride, in thepresence of a strong acid catalyst, preferably phosphoric acid-borontrifiuoride.

The compounds (VIII through XI) in the flowsheet 4 hereinafter aredescribed and claimed in my copending application Ser. No. 372,688,filed June 4, 1964, now US. Pat. No. 3,321,511, and compounds (XIVthrough XVII) in my copending application Ser. No. 372,716, filed June4, 1964, now US. Pat. No. 3,321,488.

The compound wherein R is selected from the group consisting of benzyland tertiary butyl and R is lower alkyl.

When compound (XIX) is reacted with n p-unsaturated ketones, preferablyvinyl ketones, in the presence of an alkali metal alkoxide, preferablypotassium-t-butoxide, in an inert solvent, preferably t-butanol, underan inert atmosphere, there is formed a compound of the Formula XX ingood yield which may be illustrated as follows:

wherein R is lower alkyl, R is selected from the group consisting oft-butyl and benzyl and R is selected from the group consisting ofhydrogen, lower alkyl, lower alkyl acetate and lower alkyl propionate.As specific examples, when the compoundtrans-1,2,4a,5,6,7,8,8a-octahydro 4a methyl 5 t-butoxy 2 oxo 1naphthaldehyde is treated with methylvinyl ketone in t-butanolcontaining potassium t-butoxide, there is obtained trans-1,2,4a,5,6,7,8,8a octahydro 4a methyl-S-t-butoxy-Z- oxo 1(3-oxobutyl)-1-naphthaldehyde. When methyl 5-oxo 6 heptenoate isemployed, then the product s methyl trans-l-formyl 1,2,4a,5,6,7,8,8aoctahydro 4amethyl 5 t-butoxy-5,2-dioxo-l-naphthaleneheptanoate. Whenthe corresponding benzylether of (XIX) is used, then the products arethe corresponding benzyl derivatives. Similarly, when loweralkyl-4-oxo-5-hexen0ate is used in the reaction R" is lower alkylacetate in compounds represented by generic Formula XX.

The conversion of compounds represented by (XX) is readily accomplishedby treating a solution of (XX) in a water-miscible organic solvent,preferably dioxane, with an aqueous solution of an alkali metalhydroxide, preferably sodium hydroxide, in an inert atmosphere.

As a specific example, methyl trans-1-formyl-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl 5 benzyloxy-6,2-dioxo-1-naphthaleneheptanoate, represented generically by Formula XX, ontreatment with sodium hydroxde in aqueous dioxane yieldsdl-Z,3,4,4a;8,4bu,5,6,7,8, 8a-decahydro- 821/3 methyl 8p benzyloxy 2 oxophenanthrene 1- propionic acid, represented generically by (XXI) as follows:

wherein R is lower alkyl, R' is selected from the group consisting oft-butyl and benzyl and R is selected from the group consisting ofhydrogen, lower alkyl, acetic acid and propionic acid. Where theabove-mentioned hexenoate is used in the reaction, R' for compoundsrepresented by (XXI) is acetic acid.

The compounds (XXII) of the flowsheet may be illustrated by the formula:

wherein R is lower alkyl, R is selected from the group consisting oft-butyl and benzyl and R is selected from the group consisting ofhydrogen, lower alkyl, acetic acid and propionic acid.

The reduction of compounds (XXI to XXII) is carried out with hydrogenand a hydrogenation catalyst, preferably palladium on strontiumcarbonate. Two solvent systems are employed in the reduction. When XXI(R is 'CH CH COOH or CH COOH) is the substrate, water containing oneequivalent of an alkali metal hydroxide, preferably sodium hydroxide, isused. When XXI (R' is H or lower alkyl) is the substrate, an inertsolvent, preferably benzene, is used. As a specific example, dl 8/3benzyloxy-2,3,4,4afl,4ba,5,6,7,8,8a-decahydro 8215 methyl 2oxo-phenanthrene-l-propionic acid (XXI, R is CH R is CH C H R'CHgCHgCOOH) on reduction with hydrogen in water containing oneequivalent of sodium hydroxide in the presence of palladium on strontiumcarbonate give dl-8B- benzyloxy-2,3, 4,4afl,4bu,5,6,7,8,8a,9,10dodecahydro 8afi methyl-2- oxo-phenanthrene l propionic acid (XXII, R isCH R is CH C H R'" is CH CH COOH). Where the corresponding acetic acidanalog of (XXI, R' is CH COOH) is reduced with hydrogen in water, thecorresponding acetic acid compound (XXII, R is CHgCOOH) is found.

Although the examples above are specific for R as methyl, the processesare equally applicable when R is lower alkyl and the invention includesthe compounds in which R is a lower alkyl radical.

XXV

8 In the above flowsheet R, R 1 and R are as hereinbefore defined and Ris lower alkyl.

When the compounds (XXII wherein R is or CH COOH, R is lower alkyl and Ris benzyl or t-butyl) are treated with acetic anhydride-sodium acetate,good yields of compounds (XXIII or XXIII-A) are produced. As a specificexample, the treatment ofdl-8fibenzyloxy-2,3,4,4a5,4ba,5,6,7,8,8a,9,l0-dodecahydro-8aflmethyl-Z-oxo-phenanthrene1 propionic acid (in which R is CH with acetic anhydride and sodiumacetate gives in good yield dl-l7a,fi-benzl0xy 5 hydroxy-3,5-seco-4-nor-5(10),9(11)-D-homoestradien 3 oic acid, 3,5-lactone (XXIII,in which R is CH Treatment of (XXII, where R is CH COOH), yields dl-13lower alkyl-17a-benzyloxy-1,4-bisnor-3,5-seco 5 hydroxy-D-homo-gona-5(1O),9(11)-dien 3 oic acid, 3,5-lactone.

Reduction of compounds (XXIII) with hydrogen and a hydrogenationcatalyst, preferably palladium on strontium carbonate in an inertsolvent, such as benzene, gives, in excellent yield (compounds XXIV). Asfor example, dl-l7a,;3-benzyloxy 5 hydroxy-3,5 seco-4-nor 5 (10)9(11)-D-homoestradien 3 oic acid, 3,5-lactone (XXIII, wherein R is CH onreduction gives dl-l7a,fi-benzyloxy-5-hydroxy 3,5-seco 4nor-5(10)-D-homoestren-3- oic acid, 3,5-1actone (XXIV, wherein R is CHFinally, when compounds (XXIV) are treated with a methyl magnesiumhalide, such as the bromide, and the crude product allowed to stand in amixture of acetic and hydrochloric acids, compounds (XXV) are formed ingood yield. For example, dl-17a,,B-benzyloxy-5-hydroxy- 3,5-seco 4nor-5(10)-D-homostren-3-oil acid, 3,5-lactone (XXIV, wherein R is CHgives on treatment with methyl magnesium bromide followed by acid a goodyield of dl 19 nor D homotestosterone, benzylether (compound XXV,wherein R is CH This compound (XXV) can be transformed into the knownbiologically active compound dl-l9-nor-D-homotestosterone by removingthe benzyl blocking group. This can be removed by reduction with lithiumin liquid ammonia after protecting the keto group as the ethylenedioxyketal, and subsequent acid hydrolysis of the ketal.

When the starting material isdl-l7aB-benzyloxy-5-hydroxy-3,5-seco-4-nor-5(10)-D-homogonene 3 oicacid, 3,5-lactone (compounds XXIV, wherein R is C H the final productwill be dl-l3-ethyl-l9-nor-D-homo-4-gonene- 172113-01 (compounds XXV,wherein R is ethyl and R is H).

When dl-17a,fl t butoxy 5 hydroxy 3,5 seco 4- nor-5( 10) Dhomoestren-S-oic acid, 3,5-lactone (compounds XXIV, wherein R is CH andR is t-buty1) is treated with methyl magnesium bromide followed by acid,the product is directly dl-19-nor-D-homotestosterone, the t-butylblocking group having been removed during the acid treatment.

Similarly, when the starting material is dl-l7aB-t-butoxy-13-ethyl 5hydroxy 3,5-seco 4 nor 5(10) D- homogonene-B-oic acid, 3,5 lactone(compounds XXIV, wherein R is C H and R is t-butyl) and it is carriedthrough the identical reaction sequence, the product isdll3-ethyl-19-nor-D-homo 4 gonene-17af3-ol (compounds XXV, wherein R isethyl and R is H).

The following examples describe the use of starting materials, such as2-lower alkylcyclohexane-1,3-diones to prepare the present compounds andsubsequently converting the present compounds to the biologically actived1- 19-nor-D-homotestosterone.

EXAMPLE 1 Preparation of 1,6-dioxo-A -9-ethyloctalin (II) A mixture of70.0 g. Z-ethylcyclohexane-1,3-dione (I), 2 ml. of methylvinyl ketone,0.25 g. potassium hydroxide and 250 ml. absolute methanol are heatedwith stirring under reflux for 4 hours. Methanol and excess methylvinylketone are then removed by distillation at atmospheric pressure. Benzeneis added to the residue and the distillation continued until thetemperature of the vapours is 80 C. indicating complete removal ofmethanol and water. Benzene is added to bring the volume of the solutionup to the original volume. The solution is cooled in an ice bath and 3ml. pyrrolidine is added. The solution is heated under reflux under aDean-Stark water separator for 1 hour when no more water isazeo-tropically distilling. The solution is cooled in ice, diluted withether and washed with 100 ml. water containing 15 ml. of a 10%hydrochloric acid solution, followed by 100 ml. water. The aqueousphases are combined and washed with 50ml. ether. The combined organicphases are washed with three 100 ml. portions of water, saturated brine,dried and evaporated. The residue is distilled. The main fraction boilsat 130l35 C. at 0.06 mm. The distillate is crystallized fromether-hexane to yield 46.7 g. of 1,6- dioXo-A -9-ethy1octalin. Theanalytical sample obtained by recrysta'llizations from ether-hexane hasmelting point 67.568.5 C.

The 1,6-dioxo-A -9-lower alkyloctalins are prepared by substituting theappropriate 2-lower alkylcyclohexane- 1,3-dione for theZ-ethylcyclohexane- 1,3 -dione in the above reaction. For example,the1,6 dioxo A 9 methyloctalin and 1,6-dioxo A -9-propyloctalin are'readily prepared by this procedure.

EXAMPLE 2 Preparation of 1-hydroxy-6-oxo-A -9-ethy1octalin (III) To anice-cold stirred solution of 9.6 g. of 1,6-dioxo- A -9-ethyloctalin in90 ml. absolute ethanol is added 200 mg. purified sodium borohydride.After 15 minutes, 200 mg. sodium borohydride is added and after afurther 15 minutes, 160 mg. sodium borohydride. The stirring and coolingare continued for 15 minutes and then the solution is acidified withglacial acetic acid. The ethanol is removed under reduced pressure andthe residue partitioned between chloroform and water. The aqueous phaseis Washed with chloroform and the combined organic phases washed withsodium bicarbonate solution, dried and evaporated. The residue isdistilled, the product, 1- hydroxy-6-oxo-A 9 etlhyloctalin, boils at 165C. at 0.8 mm. The oil crystallizes and the analytical sample, meltingpoint 88.0-89.5 C. is obtained by recrystallization from acetone-hexane.

By employing the appropriate 1,6-dioxo-A -9-lower alkyloctalin in theabove reaction, the corresponding 1- hydroxy-6-oxo-A -9-loweralkyloctalin is produced. For example, the corresponding-9-methyloctalin, -9-propyloctalin, -9-buty1 or isopropyloctalins may beprepared by this procedure.

EXAMPLE 3 Preparation of 1-acetoxy-6-oxo-A -9-ethyloctalin (IV) Amixture of 3.98 g. of 1-hydroxy-6-oxo-A w-ethyloctalin, 10 ml. aceticanhydride and 2ml. pyridine are heated on a steam bath for 1.5 hours.The solution is then poured into 300 ml. ice water with stirring. Afterstirring for 1 hour, the aqueous mixture is extracted with ether and theether washed with water, saturated sodium bicarbonate solution, driedand evaporated. The l-acetoxy- 6-oxo-A -9-ethyloctalin is obtained as acolorless oil, weighing 4.2 g. and is used Without further purification.

The above reaction, when condensed with the appropriate l-hydroxy 6 oxoA500) 9 lower alkyloctalin in presence of pyridine and the appropriateacyl anhydride or aroyl halide yields the corresponding 1-acyloxy-6-oxo-A -9-lower alkyloctalin, for example, l-propionyloxy- 6-oxo-A-9-propylocta1in or 1-benzyloxy-6-oxo-A 9-methyloctalin respectively.

1 0 EXAMPLE 4 Preparation of l-acetoxy-6-ethoxy-9-methyl-Ahexahydronaphthalene (V) To a solution of 44.4 grams (0.2 mole) ofl-acetoxy- 6-oxo-9-methyl-A -octalin in 44 ml. ethyl orthoformate, 4 ml.absolute ethanol and 200 ml. benzene is added 4 ml. of absolute ethanolsaturated with hydrogen chloride and the mixture is heated underrefluxing conditions for 2 hours. The mixture is cooled, diluted with anequal volume of ether and poured into 300 ml. of 5% sodium hydroxidesolution. After shaking thoroughly, the aqueous phase is discarded. Theorganic phase is washed with water, saturated brine, dried and thesolvent evapw rated. The residue, a yellow mobile oil, which can becrystallized to a colorless hydroscopic solid is essentially pure1-acetoxy-6-ethoxy-9-methyl-A -hexahydronaphthalene as determinedspectroscopically. This material is used directly for the preparation ofl-acetoxy-6-ethoxy-9- methyl-trans-A -octalin (VI).

EXAMPLE 5 Preparation of l-acetoxy-6-ethoxy-9ethyl-Ahexahydronaphthalene (V) The crude l-acetoxy-6-oxo-A -9-ethyloctalin(4.2 g.) (Example 3), 5.6 ml. ethyl orthoformate, 1 ml. absoluteethanol, 1 ml. absolute ethanol saturated with hydrogen chloride and 100m1. benzene are heated under reflux for 2 hours. The solution is cooled,diluted with ether, and washed with 100 ml. of 5% sodium hydroxidefollowed by washings with water and saturated brine. The organic phaseis dried and evaporated to yield l-acetoxy- 6-ethoxy-9-ethyl-A-hexahydronaphthalene as a pale yellow oil weighing 4.7 g. This is usedwithout further purification for the preparation of 1-acetoxy-6-ethoxy-A9-ethyl-trans-octalin.

In the above Examples 4 and 5, ethyl orthoformate is used, otherorthoformates may also be used such as methyl, propyl, butyl and thelike. Also other strong acid catalysts can be used in place of hydrogenchloride such as sulfuric acid.

When l-benzoyloxy, l-toluoyloxy or l-halobenzoyloxy, -6-oxo-9-loweralkyl-n -octalin, prepared as for example, by reacting1-hydroxy-6-oxo-9-lower alkyl-A octalin with benzoyl chloride or thelike in pyridine, is

. substituted for l-acetoxy-6-oxo-9-lower alkyl-A -oc talin, the productfrom the reaction is the corresponding l-benzoyloxy, l-toluoyloxy orl-halobenzoyloxy, -6- ethoxy-9-lower alkyl-A -hexahydronaphthalene. Whenthis starting material is employed, the products V through IX,illustrated on the flowsheet, have the l-acetoxy group replaced by thel-benzoyloxy, l-toluoyloxy or l-halobenzoyloxy group.

EXAMPLE 6 Preparation of 1-acetoxy-6-ethoxy-9-methyl-trans-A octalin(VI) 1 1 EXAMPLE 7 Preparation of 1-acetoxy-6-ethoxy-A-9-ethyl-transoctalin (VI) The crude enol ether of Example (4.7 g.) from1- acetoxy-6-oxo-A -9-ethylocta1in is dissolved in 200 ml. absoluteethanol and 1.0 g. of 2% palladium hydroxide on strontium carbonate isadded. The catalyst and compound are reduced with hydrogen atatmospheric pressure. One molar equivalent of hydrogen is absorbed. Thecatalyst is then removed by filtration and the solvent evaporated underreduced pressure. The residue consisting predominantly of1-acetoxy-6-ethoxy-A -9-ethyl-transoctalin weighs 4.7 g. and is usedwithout further purification.

Further, employing the procedure set forth in Examples 6 and 7 above andsubstituting an enol ether of the general formula:

OCOR' R2 l where R and R are lower alkyl, for the 1-acetoxy-6-ethoxy-9-methyl-A -hexahydronaphthalene of Example 6 or the1-acetoxy-6-ethoxy-9-ethyl-A -hexahydronaphthalene of Example 7, and Ris a radical selected from the group consisting of hydrogen, loweralkyl. phenyl and substituted phenyl radicals, there is produced acompound of the general formula:

OCOR

wherein R and R are lower alkyl and R is a radical as described above.

EXAMPLE 8 Preparation of 1-acetoxy-9-methyl-6-oxo-trans- Decalin (VII)The crude 1-acetoxy-6-ethoxy-9-methyl-trans A octalin is warmed on thesteam bath for 0.5 hour with 60 ml. 50% aqueous acetic acid. Aftercooling, the solution is diluted with water and extracted with ether.The ether is washed twice with water followed by saturated sodiumbicarbonate solution. The organic phase is dried and the solventevaporated. The residue is crystallized from a small volume of hexane togive 4.1 grams (61%) of 1- acetoxy-9-methyl-6-oxo-t1ans-Decalin, meltingpoint 46- 49 C.

EXAMPLE 9 Preparation of 1-acetoxy-6-oxo-9-ethyl-trans- Decalin (VII)The crude 1-acetoxy-6ethoxy-A -9-ethyl-trans-octalin (4.7 g.) preparedas in Example 7 is heated on a steam bath with ml. water and 20 ml.glacial acetic acid for 0.5 hour. The solution is cooled, diluted withwater and extracted with ether. The ether is washed with water,saturated sodium bicarbonate solution, dried and evaporated. The residueof 1-acetoxy-6-oxo-9-ethyl-trans- Decalin weighs 4.1 g. and is usedwithout further purification.

Using the procedure described in Examples 8 or 9 above and reacting acompound of the formula:

where R and R are lower alkyl and R is a radical selected from the groupconsisting of hydrogen, lower alkyl, phenyl and substituted phenylradicals, with aqueous acetic acid will yield a compound of the formula:

OCOR' 21 where R and R are as described above.

EXAMPLE 10 Preparation of 1-acetoxy-7-bromo-6-oxo-9-methyltrans-Decalin(VIII) A mixture of 1-acetoxy-6,6-ethylenedioxy-9-methyltrans-Decalin(25 g.) and 100 ml. 50% acetic acid are heated on the steam bath for 0.5hour. After cooling, the solution is diluted with water and extractedwith ether. The ether is washed with water, saturated sodiumbicarbonate, dried and evaporated. The residue of 1-acet0xy-6-oxo-9-methyl-trams-Decalin weighs 20.5 g. The keto acetate is dissolvedin 150 ml. chloroform and cooled to 0 C. To the stirred solution isadded dropwise a solution of 15.0 g. of bromine in ml. chloroform. Afterthe addition, the chloroform is removed under reduced pressure and theresidue crystallizes from ether to give 20.85 g. (74% overall) of thebromoketone. The analytical sample obtained by recrystallizations of thecrude product from acetonehexane has a melting point 147 -148 C.

The compound 1-acetoxy-7-bromo-6-oxo-9-ethyl-trans- Decalin is readilyprepared in good yield by the above procedure employing1-acetoxy-6,6-ethylenedioxy-9-ethyltrans-decalin in place of the1-acetoxy-6,6-ethylenedioxy- 9-methyl-trans-Decalin.

EXAMPLE 1 1 Preparation of 1-acetoxy-6-oxo-9-methyl-A"- trans-octalin(IX) A mixture of 27.6 g. of 1-acetoxy-7-bromo-6-oxo-9-methyl-trans-Decalin, 25 g. of dry lithium chloride and 25 g. of drylithium carbonate in 400 ml. dry dimethylformamide are heated at refluxunder nitrogen for 2 hours. The solution is cooled, diluted with waterand extracted with ether. The ether is washed twice with water,saturated brine, dried and evaporated. The residue crystallizescompletely and weighed 18.0 g. (89%). This material is sufficiently purefor the next reaction. An analytical sample obtained byrecrystallization from ether-hexane has a melting point 62.5-63.5 C.

This process is also advantageously employed to produce1-acetoxy-6-oxo-9-ethyl-A -trans-octalin in high yield by simplysubstituting 1-acetoxy-7-bromo-6-oxo-9-ethyltrans-Decalin for 1 acetoxy7-bromo-6-oxo-9-methyltrans-Decalin in the reaction.

EXAMPLE 12 Preparation of 1-hydroxy-6-oxo-9-methyl-A trans-octalin (X) Amixture of 17.4 g. of 1-acetoxy-6-oxo-9-methyl-A trans-octalin in ml.ethanol and 50 g. potassium bicarbonate in ml. water are heated underreflux for 5.5 hours. The mixture is cooled, diluted with water andextracted with ether. The ether is washed with water and saturatedbrine, dried and evaporated. The residue is crystallized fromether-hexane to give 10.2 g. of 1-hydroxy-6- oxo-9-methyl-A'-trans-octalin, melting point 8688 C. The analytical sample has meltingpoint 88-89 C.

Substituting 1-acetoxy-6-oxo-9-ethyl-A -trans-octalin for1-acetoxy-6-oxo-9-methyl-A -trans-octalin gives the corresponding9-ethyl derivative (X) in good yield.

13 EXAMPLE 13 Preparation of 1-t-butoxy-6-oxo-9-methyl-A trans-octalin(XI) To 25 ml. of liquid isobutylene containing 0.5 ml. of 100%phosphoric acid saturated with boron trifluoride is added 5.0 g. of1-hydroxy-6-oxo-9-methyl-A -trans-octalin in 25 ml. dry methylenechloride. The mixture is shaken overnight at room temperature. Aftercooling the mixture in an ice-methanol bath, excess isobutylene isremoved by a stream of dry nitrogen and the residue is dissolved inmethylene chloride. The solution is washed thoroughly with saturatedsodium bicarbonate solution, dried and evaporated. The residue isdissolved in hexane and passed through a plug of neutral alumuina.Evaporation of the solvent yielded 5.7 g. (87%) of crystalline t-butylether melting point 72 -73 C.

The compound 1-t-butoxy-6-oxo-9-ethyl-A' -trans-octalin is prepared inaccordance with the above procedure employing as the starting material1-hydroxy-6-oxo-9- ethyl-A' -trans-octalin in the place of1-hydroxy-6-oxo-9- methyl-A' -trans-octalin.

EXAMPLE 14 Preparation of 1-acetoxy-6,6-ethylenedioxy-9-methyl-trans-Decalin (XII) The crude1-acetoxy-9-methyl6-oxo-trans-Decalin derived from 16 grams crude1-acetoxy-6-ethoxy-9-methy1- A hexahydronaphthalene by the series ofreactions decsribed in Examples 4, 6 and 8 without purification of anyintermediates is heated in 250 m1. benzene containing 16 grams ethyleneglycol and 200 mg. p-toluenesulphonic acid under a Dean-Stark waterseparator for 4 hours. The cold benzene solution is diluted with 200 ml.ether and then washed successively with saturated sodium bicarbonatesolution, water and saturated brine. After drying the organic phase, thesolvents are removed under reduced pressure. The residue is diluted withan equal volume of hexane and kept at C. overnight. The crystalline massis removed by filtration and washed with ml. cold hexane. Total yield ofl-acetoxy-6,6-ethy1enedioxy-9 methyltrans-Decalin is 9.7 grams (57%based on enol ether of Example 4), melting point 116117 C. is obtained.

In the above reaction ethylene glycol is used to protest the keto group,however, other alcohols can 'be used such as. propandiol.

EXAMPLE 15 Preparation of 1acetoxy-6,6-ethylenedioxy-9-ethyl-trans-Decalin (XII) A solution of crude1-acetoxy-6-oxo-9-ethyl-trans-Decalin (2.05 g.) prepared as in Example 9dissolved in 100 ml. benzene containing 2.05 g. ethylene glycol and 100mg. p-toluenesulphonic acid is heated under reflux under a Dean-Starkwater separator until no more water is azeotropically removed (4.5hours). The solution is cooled, diluted with ether and washed withsaturated sodium bicarbonate solution. The organic phase is then washedwith water followed by saturated brine, dried and the solvents removedunder reduced pressure. The residue is crystallized from hexane to give1-acetoxy-6,6-ethylenedioxy-9-ethy1-trans-Decalin. The analytical sampleobtained by recrystallizations of the product from acetonehexane has amelting point 7 8.579.5 C.

A compound of the formula:

OCOR

as exemplified by Examples 14 and 15 above, where R is lower alkyl and Ris hydrogen, lower alkyl, phenyl or substituted phenyl radical areprepared by reacting a compound of the formula:

OCOR' 2 I where R and -R' are as described above, with benzene, ethyleneglycol and an acid such as p-toluenesulphonic acid.

EXAMPLE 16 Preparation of1-hydroxy-6,6-ethylenedioxy-9-methyltrans-Decalin (XIII) A mixture of10.72 grams (0.04 mole) of l-acetoxy-6,6-ethylenedioxy-9-methyl-trans-Decalin, ml. ethanol and 50 ml. 2 Npotassium hydroxide solution are heated under refluxing conditions for 2hours. Most of the ethanol is removed by distillation under reducedpressure, the residue is diluted with Water and extracted with ether.The ether is washed with water, saturated brine, dried and evaporated.The residue crystallizes completely to give 7.9 grams (84% yield) of 1hydroxy 6,6-ethylenedioxy- 9 methyl-trans-Decalin, melting point 7172 C.

Employing the procedure of this example and substituting a l acyloxyorl-aroyloxy-, -6,6-ethylenedioxy-9- lower alkyl-trans-Decalin for .1acetoxy 6,6-ethylenedioxy 9 methyl-trans-Decalin will yield thecorresponding 1 hydroxy 6,6 ethylenedioxy 9 lower alkyltrans-Decalin.The l-hydroxy 6,6 ethylenedioxy-9- ethyl-trans-Decalin prepared by thismethod is a crystalline solid, melting point 9596 C.

EXAMPLE 17 Preparation of 1benzyloxy-6,6-ethylenedioxy-9methyltrans-Decalin (XIV, R =CH A mixture of 63 ml. benzyl chloride,10.85 g. l-hydroxy 6,6 ethylenedioxy 9 methyl-trans-Decalin (XIII, R isCH and 11.05 g. of a 54% suspension of sodium hydride in mineral oil isstirred and gradually heated. At -125 C. a vigorous exothermic reactiontakes place. When the reaction has subsided, a temperature of C. ismaintained for 1 hour. The mixture is diluted with benzene and filtered.The benzene and excess benzyl chloride are removed under reducedpressure and the residue distilled. The product,1-benzyloxy-6,6-ethylenedioxy-9-methyl-trans-Decalin is distilled at176182 C. at 0.5 mm., (13.0 g.). The product (XIV, R is CH crystallizescompletely and the analytical sample (from hexane) has a melting point8383.5 C.

When 1 hydroxy 6,6 ethylenedioxy 9 ethyltrans-Decalin (XIII, R is C H isused in the reaction with benzyl chloride, the product is1benzl0xy-6,6-ethylenedioxy 9 ethyl-trans-Decalin (XIV, R is C H whichdistills at L82-184 C. at 0.05 mm.

EXAMPLE 18 Preparation of 1-benzyloxy6-oxo-9-methyl-trans- Decalin (XV,R =CH To a solution of 130 g. of 1-benzyloxy-6,o-ethylenedioxy-9-methyl-trans-Decalin (XIV, R is CH in 500 ml. glacial acetic acid isadded 300 ml. water and the mixture heated on the steam bath for 0.5hour. Approximately 200 ml. glacial acetic acid are added and theheating continued for 1.5 hours. After cooling the mixture, it isdiluted with water and extracted with ether. The ether is washed withwater, saturated sodium bicarbonate solution, dried and evaporated. Theresidue is distilled and the product has boiling point 157 C. at 0.03mm. The product can be crystallized from hexane at -10 C. to a solidmelting point 4647 C.

When I benzyloxy 6, 6 ethylenedioxy 9 ethyltrans-Decalin (XIV, R is C His hydrolyzed in the same way as described above, the product isl-benzyloxy- 6-oxo-9-ethyl-trans-Decalin (XV, R is C H EXAMPLE 19Preparation of 1-benzyloxy-7-bromo-6-oxo-9-methyltrans-Decalin (XVI, R=CH A stirred solution of 38.35 g. of 1-benzyloxy-6-oxo-9-methyl-trans-Decalin in 500 ml. chloroform was cooled to C. and then25.9 g. of bromine in 175 ml. chloroform is added dropwise at such arate that there is never more than a small amount of free brominepresent. After the addition, the solution is poured into a saturatedaqueous sodium bicarbonate solution. The two phases are well shaken, thechloroform layer separates, is dried and evaporated. The residue (51.0g.) consisting mainly of 1- benzyloxy7-bromo-6-oxo-9-methyl-trans-Decalin (XVI, R is CH is used withoutfurther purification. The compound can be crystallized fromacetone-hexane and the analytical sample melted at ll2-1l3 C.

When 1 benzyloxy 6 oxo-9-ethyl-trans-Decalin (XV, R C H is brominated inthe same way, the product is 1 benzyloxy 7bromo-6-oxo-9-ethyl-transdecalin (XVI, R is C H which has melting point139- 140 C.

EXAMPLE 20 Preparation of 1-benzyloxy-6-oxo-9-methylA -transoctalin(XVIIR =CH The crude l benzyloxy 7 bromo-6-oxo-9-methyltrans-Decalin(51.0 g.) prepared as in Example 19 is dissolved in 600 ml. drydimethylformamide and 35 g. of dry lithium carbonate and 35 g. of drylithium carbonate added. The mixture is stirred and heated at refluxunder nitrogen for two hours. The mixture is cooled and most of thesolids removed by filtration. The filtrate is diluted with water andextracted with ether, then ether washed with water, saturated brine,dried and evaporated. The residue is distilled to give1-benzyloxy-6-oxo-9-methyl- A' -transoctalin (XVII, R is CH as a paleyellow oil, boiling point 170 C. at 0.5 mm.

When 1 benzyloxy 6 oxo 7 bromo 9 ethyltrans-Decalin (XVI, R is C H isdehydrobrominated as described above, the product is 1 benzyloxy 6 oxo-9 ethyl A -trans-octalin (XVII, R is C H which distills at 165-170 C. at0.1 mm.

EXAMPLE 21 Preparation of transl,2,4a,5,6,7,8,8a-octahydro-4amethyl-5-t-butoxy-2-oxo-l-naphthaldehyde(XIX, R2:CH3,

To a stirred suspension of dry sodium methoxide (from 0.74 g. sodium) indry benzene under nitrogen is added 4.5 ml. of redistilled ethyl formatein a gentle stream. After stirring at room temperature for 0.5 hour, themixture is cooled to 0 C. and 2.36 g. of 1-t-butoxy-6-oxo-9-methyl-N-trans-octalin in 20 ml. dry benzene is added dropwise.The solution is then stirred overnight at room temperature. Water andether are added to the mixture. The water is separated and the organicphase extracted twice with 1 N potassium hydroxide. The combined aqueousphases are acidified with 2.5 M sodium dihydrogen phosphate solution andthoroughly extracted with ether. The ether is washed with water,saturated brine, dried and evaporated. The residue (2.55 g.) consistingof trans-1,2,4a,5,6,7,8,Sa-octahydro-4a-methyl-5-tbutoxy 2oxo-l-naphthaldehyde (XIX, R is CH R is C(CH is used without furtherpurification.

EXAMPLE 22 Preparation of trans 1,2,4a,5,6,7,8,8aoctahydro-4amethyl-S-benzyloxy-Z-oxo-l-naphthaldehyde (XIX, RZ'ZCH3,R'TICHZCGH5) The above is prepared from 2.86 g. of crudel-benzyloxy-6-oxo-9-methyl-fl-octalin (XV, R is CH R is 1a CH C l-Iethylformate (4.5 ml.), and sodium methoxide (from 0.74 g. sodium) in amanner similar to that described for the t-butoxy analog in Example 21.The trans- 1,2,4a,5,6,7,8,8a-octahydro-4a-methyl 5 benzyloxy-2-oxo-l-naphthaldehyde (XIX, R is CH R is CH C H (3.1 g.) is obtained as apale yellow oil and used directly. When the reactions described inExamples 21 and 22 use as starting materials the ethyl analog (R is C Hthe products are the corresponding ethyl compounds.

EXAMPLE 23 Preparation of trans 1,2,4a,5,6,7,8,8a-octahydro 4a- Thecrude l-t-butoxy-5-formyl-6-oxo-9-methyl-A -transoctalin (2.55 g.) isdissolved in 100 ml. dry benzene and the solvent removed to removetraces of water. This procedure is repeated. The residue is dissolved inml. dry t-butanol and 0.87 g. freshly distilled methylvinyl ketoneadded. The air is displaced by nitrogen, the solution cooled down in anice bath and 1 ml. of a 1 M solution of potassium t-butoxide int-butanol is added. The solution is left at room temperature overnight.Ether and water are added and the aqueous phase thoroughly extractedwith ether. The ether is Washed with water, saturated brine, dried andevaporated. The residue, a iscous pale yellow oil, oftrans-1,2,4a,5,6,7,8,8a-octahydro- 4a methyl 5 t butoxy 2 oxo l(3-oxobutyl)-lnaphthaldehyde (XX, R is CH R is C(CH R is H) is usedwithout further purification.

EXAMPLE 24 Preparation of trans-1,2,4a,5,6,7,8,8a octahydro 4amethyl 5benzyloxy 2 0x0 1 (3-oxobutyl)-1- naphthaldehyde (XX, R =CH R'=CH C H R"E From trans 1,2,4a,5,6,7,8,8a-octahydro 4a methyl- S-benzyloxy 2 oxo 1naphthaldehyde (XIX, R is CH R is CH C H 3.1 g. crude as described inExample 22, 0.87 g. freshly distilled methylvinyl ketone and 1 ml. of a1 M solution of potassium t-butoxide in t-butanol there is obtained byfollowing the procedure as described in Example 23,trans-1,2,4a,5,6,7,8,8a-octahyduro-4a-methyl 5 benzyloxy 2 oxo l(3-oxobutyl)- l-naphthaldehyde, is obtained as a viscous pale yellow oilwhich is used without further purification.

When the procedures described in Examples 23 and 24 are carried throughwith the ethyl analog, the products obtained are the 4a-ethylnaphthaldehydes.

EXAMPLE 25 Preparation oftrans-1,2,4a,5,6,7,8,8a-octahydro-4a-methyl-S-benzyloxy 2 oxo 1-(3-oxopentyl)-1-naphthaldehyde (XX, R=CH R=CH C H R"=CH The abovecompound is prepared from trans-l,2,4a,5,- 6,7,8,8a-octahydro 4a methyl5 benzyloxy-2-oxo-1- naphthaldehyde (XIX, R is CH R is CH C H andethylvinyl ketone by the procedure described in Example 24.

EXAMPLE 26 Preparation of methyl trans-l-formyl-1,2,4a,5,6,7,8,8a

octahydro 4a methyl 5 t butoxy 5,2 dioxo lnaphthaleneheptanoate (XX,R=CH R'=C(CH R=CH CH COOCH The crude trans-1,2,4a,5,6,7,8,8a octahydro4amethyl 5 t butoxy 2 oxo 1 naphthaldehyde prepared in Example 21 isdissolved in 5 ml. dry t-butanol and 1.87 g. methyl 5-oxo-6-heptenoateadded. After cooling the solution under a nitrogen atmosphere, 1 ml. ofa 1 molar solution of potassium t-butoxide in t-butanol is added and themixture kept at room temperature overnight. The solution is diluted withwater and ether and the aqueous phase thoroughly extracted with ether.The

ether is washed with water, and saturated brine, dried and evaporated.The residue of methyl trans-1-f0rmyl-1,2,4a, 5,6,7,8,8a octahydro 4amethyl 5 t butoxy 6,2- dioxo 1 naphthalenehepta-noate (XX, R is CH R isC(CH R" is CH CH COOCH is obtained as a viscous, pale yellow oil, and isused without further purification. The methyl acetate analog i.e. whereR" is CH COOCH can also be prepared by this procedure using methyl4-oxo-5-hexenoate instead of 5-oxo-6- heptenoate.

EXAMPLE 27 Preparation of methyl trans 1 formyl 1,2,4a,5,6,7,8,

8a octahydro 4a methyl 5 benzyloxy 5,2-dioxol-naphthaleneheptanoate (XX,R :CH R=CH C H R"=CH CH COOCH This is prepared from the crudetrans-1,2,4a,5,6,7,8,8aoctahydro 4a methyl 5 benzyloxy 2 oxo 1-naphthaldehyde, 3.1 g., described in Example 22, 1.87 g. of methyl5-oxo-6-heptenoate and 1 ml. of a 1 M solution of potassium t-butoxidein t-butanol by the procedure described in Example 26.

The product, methyl trans 1 formyl-1,2,4a,5,6,7, 8,8aoctahydro 4a methyl5 benzyloxy 6,2 dioxo 1- naphthaleneheptanoate (XX, R is CH R is CH C HR is CH CH COOCH is obtained as a pale yellow viscous oil and was usedin this form without further purification. The methyl acetate analog ofthe above compound, i.e. where R" is CHZCOOCHg, can be prepared by thisprocedure with methyl 4-oxo-5-hexenoate in place of methyl5-oxo-6-heptenoate.

EXAMPLE. 28

Preparation of dl 8,8 t butoxy Sal; methyl 4,4a5, 4ba,5,6,7,8,8aoctahydro 2(3H) phenanthrone (XXI, R =CH R"=C(CH R'=H) The crude trans1,2,4a,5,6,7,8, 8a-octahydro 4amethyl 5 t butoxy 2 oxo 1 (3 oxobutyl)-1-naphthaldehyde prepared in Example 23 is dissolved in 25 ml. dioxane andcooled to C. A solution of 1.7 g. potassium hydroxide in 25 ml. water isadded and the air displaced by nitrogen. After standing at roomtemperature for 3 hours, ether and water are added to the mixture andthe aqueous phase thoroughly extracted with ether. The ether is washedwith water and saturated brine, dried and evaporated. The residue iscrystallized from etherhexane. The analytical sample crystallized fromhexane has the melting point 134135 C.

EXAMPLE 29 Preparation of dl 8,3 benzyloxy 8:11p methyl 4,4215-4ba,5,6,7,8,8a octahydro 2(3H) phenanthrone (XXI, R =CH R' =CH C H R=H)The above is prepared from trans 1,2,4a,5,6,7,8,8aoctahydro 4a methyl 5benzyloxy 2 0x0 1 (3- oxobutyl) 1 naphthaldehyde (prepared as in Example24) in 25 ml. dioxane and 1.7 g. potassium hydroxide in 25 ml. water asdescribed in Example 28. The crude product is chromatographed on aluminato yield ,dl-Sfl-benzyloxy 8a5 methyl 4,4afl,4ba,5,6,7,8,8a octahydro-2(3H)-phenanthrone. An analytical sample, recrystallized from methanol,has melting point 1091l0 C.

EXAMPLE This is prepared from trans-1,2,4a,5,6,7,8,8a-octahydro- 4amethyl 5 benzyloxy 2 oxo-l-(3-oxopenty1)-lnaphthaldehyde (XX, R is CH Ris CH C H by the procedure described in Example 28 to give the productdl 8p -benzyloxy 8a,8,1-dimethyl-4,4afl,4ba,5, 6,7,8,8a-

l 8 octahydro-2(3H)-phenanthrone (XXI, wherein R is CH R is CH2C6H5 andR, is CH3).

EXAMPLE 31 Preparation of d1 2,3,4,4a5,4boc,5,6,7,8,8a decahydro- 8a/3methyl 8B t butoxy 2 oxo-phenanthrenel-propionic acid (XXI, R CH R'=C(CHR=CH CH COOH) Crude methyl trans-l-formyl-l,2,4a,5,6,7,8,8a-octahydro 4amethyl 5-t-butoxy-6,2-dioxo-1-naphthaleneheptanoate (3.0 g.) prepared inExample 26 is dissolved in 15 ml. dioxane and 30 ml. of a 1.6 M solutionof sodium hydroxide added. The mixture is stirred overnight at roomtemperature under nitrogen. The solution is diluted with Water andextracted With ether. The aqueous phase is acidified with 6 N sulphuricacid and rapidly extracted with ether. The ether is washed twice withwater followed by saturated brine solution. The ether is dried andevaporated. The residue (2.0 g.) is exhaustively extracted with boilingcyclohexane. The cyclohexane is evaporated and the residue crystallizedfrom acetonitrile. The analytical sample recrystallized from the samesolvent has melting point 88-89 C. The acetic acid analog of thiscompound, where R' is -CH COOH, may be prepared employing the methylacetate analog of compound (XX) in the reaction.

EXAMPLE 32 Preparation of dl-2,3,4,4a,8,4ba,5,6,7,8,8a-decahydro-8a/3-methyl 8,8 benzyloxy 2 oxo phenanthrenel-propionic acid (XXI, RFCH R==CHC H -R CH CH COOH) This is prepared from the crude methyltrans-l-formyll,2,4a,5,6,7,8,8a octahydro 4a methyl-S-benzyloxy-6,2-dioxo-l-naphthaleneheptanoate described in Example 27 in 15 ml.dioxane and 30 ml. of a 1.6 M solution of sodium hydroxide as describedin Example 31. The product, dl 2,3,4,4afi,4ba,5,6,7,8,8adecahydro-Safi-rnethyl- 8p benzyloxy 2 oxo phenanthrene-l-propionic acidis obtained as a crystalline solid. Recrystallization from acetonitrilegives an analytical sample melting point 158- 159" C.

EXAMPLE 33 Preparation of dl-8fl-t-butoxy-8aB-methyl-4,4a,8,4ba,5,6,7,8,8a,9,10 decahydro-2(3H) phenanthrone, (XXII wherein R is CH R is C(CHR is H) A suspension of 25 mg. of 2% palladium hydroxide on strontiumcarbonate in 5 ml. dry benzene is reduced with hydrogen :at atmosphericpressure. When the reduction is complete 54.4 mg. ofdl-Sfi-t-butoxy-8aB-methyl-4,4a[3, 4ba,5,6,7,8,8a-octahydro 2*(3-H)phenanthrone is added and the reduction continued. After 7 minutes, 4.54ml. of hydrogen has been absorbed and there is no further absorption.The catalyst is removed by filtration and the solvent removed underreduced pressure. The residue crystallized and the solid isrecrystallized from hexane at l0 C. to givedl-8,8-t-butoxy-8a/3-methyl-4,4ap,4bu,5, 6,7,88a,9,10-decahydro-2(3H)-phenanthrone, melting point 97-98 C.

EXAMPLE 34 Preparation of dl benzyloxy 821B methyl 4,4afi,4boc,5,6,7,8,88.,9,l0 decahydro 2(3H)-phenanthrone (XXII, wherein R isCH R is CH C H and R is H) Reduction of 43.7 mg. of dl-8fibenzyloxy-8afi-methyl- 4,4afl,4ba,5,6,7,8,8a octahydro2(3H)-phenanthrone in benzene with 25 mg. of 2% palladium hydroxide onstrontium carbonate as described in Example 33 gives d1- 86 benzyloxy821p methyl 4,4afl,4ba,5,6,7,8,8a,9,10- decahydro-Z(3H)-phenanthrone,melting point 101 102 C.

1 9 EXAMPLE 35 Preparation ofdl-8fl-benzyloxy-2,3,4,4a;8,4ba,5,6,7,8,8a,9,

10 dodecahydro 8211i methyl 2-oxo-phenanthrene- 1 propionic acid (XXIwherein R is CH R is CH C H and R' is CH CH COOH) A suspension of 1.0 g.of 2% palladium hydroxide on strontium carbonate is reduced in 30 ml.water with hydrogen at atmospheric pressure and room temperature. Asolution of 3.94 g. of dl-8fl-benzyloxy-2,3,4,4a 3,4ba,5, 6,7,8,8adecahydro 8afl methyl 2-oxo-phenanthrenel-propionic acid in 10 ml. of 1N sodium hydroxide is added. When 1 molar equivalent of hydrogen hasbeen absorbed, the catalyst is removed by filtration and the aqueousphase acidified with dilute hydrochloric acid. The aqueous phase isthoroughly extracted with ether, the ether washed with water, saturatedbrine, dried and evaporated. The residue (4.0 g.) of crudedl-8fi-benzyloxy-2,3, 4,4a 8,4ba,5,6,7,8,8a,9,10 dodecahydro Sarimethyl-2- oxo-phenanthrene-l-propionic acid is used without furtherpurification.

The procedures detailed in Examples through for the methyl compounds RCH in generic formulas are equally useful when R is C H and yield thecorresponding product. This also applies where R" is methyl acetate (XX)and following reactions yield XXI and XXII where R is CH COOH.

EXAMPLE 36 Preparation of 11 l7a/3-benzyloxy-5-hydroxy-3,5-seco-4- nor5(10),9(11) D-homoestradien 3-oic acid, 4,5- lactone (XXIII wherein R isCH and R is CH C H A solution of 4 g. ofdl-8,8-benzyloxy-2,3,4,4a,8,4ba,5, -6,7,8,8a,9,10 dodecahydro8afl-methyl-2-oxo-phenanthrene-l-propionic acid in ml. acetic anhydrideand 50 mg. anhydrous sodium acetate is heated under reflux undernitrogen for 4 hours. The solvents are evaporated under reduced pressureand the residue dissolved in ether and water. The aqueous phase isthoroughly extracted with ether, the ether phase combined and washedsuccessively with 1 M sodium carbonate solution, water and saturatedbrine. The ether is separated, dried and evaporated. The residue iscrystallized from ether to give dl-17afi-benzyloxy 5 hydroxy 3,5 seco 4nor-5(10),9(11)-D- homoestradien-S-oic acid, 3,5-lactone, melting point130 131 C.

EXAMPLE 37 Preparation of d1-17afi-benzyloxy-S-hydroxy-B,5-seco-4- nor 5(10) D homoestren 3-oic acid, 3,5-lactone (XXIV, wherein R is CH; and Ris CH C H A suspension of 0.5 g. of 2% palladium hydroxide on strontiumcarbonate in 40 ml. dry benzene is reduced with hydrogen at roomtemperature and atmospheric pressure. Then 1.76 g. of dl-17a8-benzyloxy-5-hydoxy-3,5-seco-4- nor-5(10),9(11)-D-homoestradien-3-oicacid, 3,5-lactone in 40 ml. dry benzene is added and the reductioncontinued. During 22 hours, 135 ml. of hydrogen had been absorbed andthe catalyst is then removed by filtration and the solvent evaporated.The residue is dissolved in ether and percolated through a plug offlorisil. The fiorisil is washed with more ether and the combined ethersolutions evaporated and the residue crystallized from an etherhexanemixture to give dl-17afl-benzyloxy-5-hydroxy-3,5- seco 4 nor5(10)-D-homoestren-3-oic acid, 3,5-lactone, melting point 123-124" C.

EXAMPLE 3 8 Preparation of dl-19-nor-D-homotestosterone, benzyl ether(XXV wherein R is CH and R is CH C H A solution of 0.5 g. dl-l7a8-benzyl0xy-5-hydroxy-3,5- seco 4 nor 5(10) D homoestren 3 oic acid,3,5-lactone in ml. ether and 30 m1. benzene is cooled to 50 C. undernitrogen and 2 ml. of a 3 M solution of methyl magnesium bromide inether is added with stirring over 20 minutes. After stirring a further 1hour at 50 C., 2 N hydrochloric acid is added and the mixture warmed toroom temperature. The organic phase is diluted with benzene and theaqueous phase thoroughly extracted. The organic phase is Washed with a 1M sodium carbonate solution, water, dried and evaporated to give 0.55 g.of a colorless oil. The oil is dissolved in 15 ml. glacial acetic acidand 1.5 ml. concentrated hydrochloric acid is added. The solution isallowed to stand under nitrogen at room temperature for 48 hours. Thesolvents are removed under reduced pressure and the residue dissolved inbenzene. The benzene is Washed with saturated sodium bicarbonate, water,saturated brine, dried and evaporated to give a crystalline residue.This is recrystallized from ethanol to give 300 mg.19-nor-D-homotestosterone, benzyl ether, melting point -188 C. A puresample is prepared by recrystallization from a chloroform-ethanolmixture. The analytical sample has melting point 194-195 C.

The procedures outlined in Examples 36, 37 and 38 are equally applicablewhen R in the generic formula is ethyl. In this instance the productsare the corresponding ethyl compounds.

What is claimed is:

1. The compound dl 8,9 t butoxy Safi methyl-4,4afi,4ba,5,6,7,8,8a-octahydro-2(3H)-phenanthrone.

2. The compound d1 813 benzyloxy 8aB methyl- 4,4a/9,4ba,5,6,7,8,8a-octahydro-2 3H) -phenanthrone.

3. The compound dl 8B benzyloxy 8ap,1 dimethyl- 4,4a}3,4bx,5,'6,7,8,8a-octahydro-2(3H)-phenanthrone.

References Cited UNITED STATES PATENTS 2,687,435 8/1954 Woodward 260-5862,720,542 11/1955 Newhall et a1 260590 2,764,616 9/1956 Hoehn et a].260590 2,810,729 10/1957 Sarett 260340.9

BERNARD HELFIN, Primary Examiner G. A. SCHWARTZ, Assistant Examiner US.Cl. X.R. 260-590, 999

